Purdue University Institute for Drug Discovery , 720 Clinic Drive , West Lafayette , Indiana 47907 , United States.
On Target Laboratories , 1281 Win Hentschel Blvd , West Lafayette , Indiana 47906 , United States.
J Med Chem. 2018 Nov 8;61(21):9637-9646. doi: 10.1021/acs.jmedchem.8b01115. Epub 2018 Oct 19.
Because the most reliable therapy for cancer involves quantitative resection of all diseased tissue, considerable effort has been devoted to improving a surgeon's ability to locate and remove all malignant lesions. With the aid of improved optical imaging equipment, we and others have focused on developing tumor-targeted fluorescent dyes to selectively illuminate cancer nodules during surgery. We describe here the design, synthesis, optical properties, in vitro and in vivo tumor specificity/affinity, pharmacokinetics, preclinical toxicology, and some clinical application of a folate receptor (FR)-targeted NIR dye (OTL38) that concentrates specifically in cancer tissues and clears rapidly from healthy tissues. We demonstrate that OTL38 binds FR-expressing cells with ∼1 nM affinity and eliminates from receptor negative tissues with a half-time of <30 min. We further show that OTL38 enables visualization of malignant lesions at concentrations less than 100-fold those required to elicit signs of toxicity. Since OTL38 also provides excellent tumor contrast in both murine tumor models and human cancer patients, we conclude that OTL38 constitutes an excellent NIR dye for fluorescence-guided resection of malignant lesions in cancer patients.
由于癌症最可靠的治疗方法涉及定量切除所有病变组织，因此人们投入了相当大的精力来提高外科医生定位和切除所有恶性病变的能力。在改进的光学成像设备的帮助下，我们和其他人专注于开发肿瘤靶向荧光染料，以便在手术过程中选择性地照亮癌症结节。我们在这里描述了一种叶酸受体 (FR)-靶向近红外染料 (OTL38) 的设计、合成、光学性质、体外和体内肿瘤特异性/亲和力、药代动力学、临床前毒理学以及一些临床应用，该染料特异性地集中在癌症组织中，并迅速从健康组织中清除。我们证明 OTL38 以约 1 nM 的亲和力与表达 FR 的细胞结合，并以小于 30 分钟的半衰期从受体阴性组织中消除。我们进一步表明，OTL38 能够以低于引起毒性迹象所需浓度 100 倍的浓度可视化恶性病变。由于 OTL38 还在小鼠肿瘤模型和人类癌症患者中提供了出色的肿瘤对比度，因此我们得出结论，OTL38 是用于荧光引导切除癌症患者恶性病变的理想近红外染料。
